Novel nicotinamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors

ABSTRACT

The invention relates to novel nicotinamide pyridinureas as VEGF receptor kinase inhibitors, their production and use as pharmaceutical agents for preventing or treating diseases that are triggered by persistent angiogenesis.

This application claims the benefit of the filing date of U.S.Provisional Application Ser. No. 60/626,918 filed Nov. 12, 2004.

The invention relates to novel anthranilamide pyridinureas as VEGFreceptor kinase inhibitors, their production and use as pharmaceuticalagents for preventing or treating diseases that are triggered bypersistent angiogenesis.

Many diseases are known to be associated with persistent angiogenesis,for example, diseases such as tumor- or metastases-growth; psoriasis;arthritis, such as rheumatoid arthritis, hemangioma, endometriosis,angiofibroma; eye diseases, such as diabetic retinopathy, neovascularglaucoma; renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathicsyndrome, transplant rejections and glomerulopathy; fibrotic diseases,such as cirrhosis of the liver, mesangial cell proliferative diseasesand arteriosclerosis.

Lymphangiogenesis is a process accompanying tumor growth and metastases.It is prominent in lymphedema, lymphangiectasia, lymphangioma, andlymphangiosarcoma and in asthmatic disease, where lymph vessels arechronically overexpressed in the lung.

Persistent angiogenesis is induced by the factor VEGF via its receptors.In order for VEGF to exert this action, it is necessary that VEGF bindto the receptor, and that a tyrosine phosphorylation is induced.

Direct or indirect inhibition of the VEGF receptor can be used forpreventing or treating such diseases and other VEGF-induced pathologicalangiogenesis and vascular permeable conditions, such as tumorvascularization. For example, it is known that the growth of tumors canbe inhibited by soluble receptors and antibodies against VEGF, anexample for the latter being Avastin® whose treatment paradigm has beenintroduced in human cancer therapy.

Anthranilic acid amides effective in the treatment of psoriasis;arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; eyediseases, such as diabetic retinopathy, neovascular glaucoma; renaldiseases, such as glomerulonephritis, diabetic nephropathy, malignantnephrosclerosis, thrombic microangiopathic syndrome, transplantrejections and glomerulopathy; fibrotic diseases, such as cirrhosis ofthe liver, mesangial cell proliferative diseases, arteriosclerosis,injuries to nerve tissue, and for inhibiting the reocclusion of vesselsafter balloon catheter treatment, in vascular prosthetics or aftermechanical devices are used to keep vessels open, such as, e.g., stents,have been reported in WO 00/27820.

Anthranilic acid amides that are effective in the treatment of tumor ormetastasis growth, psoriasis, Kaposi's sarcoma, restenosis, such as,e.g., stent-induced restenosis, endometriosis, Crohn's disease,Hodgkin's disease, leukemia; arthritis, such as rheumatoid arthritis,hemangioma, angiofibroma; eye diseases, such as diabetic retinopathy,neovascular glaucoma; renal diseases, such as glomerulonephritis,diabetic nephropathy, malignant nephrosclerosis, thrombicmicroangiopathic syndrome, transplant rejections and glomerulopathy;fibrotic diseases, such as cirrhosis of the liver, mesangial cellproliferative diseases, arteriosclerosis, injuries to nerve tissue, andfor inhibiting the reocclusion of vessels after balloon cathetertreatment, in vascular prosthetics or after mechanical devices are usedto keep vessels open, such as, e.g., stents, as immunosuppressiveagents, as a support in scar-free healing, in senile keratosis and incontact dermatitis have also been reported in WO 04/13102.

There is, however, a desire to produce compounds that are as efficaciousas possible in as broad a range of indications as possible. A constantblockade of VEGF mediated signal transduction is desirable in order toreduce persistent angiogenesis and lymphangiogenesis. Suitable compoundsfor longer term treatment should exhibit little or no drug-druginteraction potential. The Cytochrome P450 isoenzymes play a pivotalrole in the degradation of pharmaceutical agents. The problem is alsocomplicated by the fact that patients may express different relativeamounts of the isoenzymes. An inhibition of these isoenzymes may resultin undesirable pharmaceutical agent interactions, especially in the caseof multimorbid patients (patients with multiple disease conditions). Forexample, inhibition of the Cytochrome P450 isoenzymes responsible formetabolisation of the parent agent could lead to toxic systemicconcentrations. A further problem exists in combination therapy withother medications, whereby inhibition of the Cytochrome P450 isoenzymesresponsible for metabolising the co-medications could lead to toxicsystemic concentrations of the co-medication. This is especially thecase for co-administered cytostatics in the case of cancer therapy.

Thus, it has now surprisingly been found that compounds of generalformula (I), as described below, have more advantageous physico-chemicaland/or pharmacokinetic properties and prevent, for example, tyrosinephosphorylation or stop persistent angiogenesis and thus the growth andpropagation of tumors, whereby they are distinguished in particular by apotent inhibition of VEGF receptor kinases and a reduced potential fordrug-drug interactions, specifically a reduced inhibition of cytochromeP450 isoenzymes 2C9 and 2C19.

The compounds of formula (I) are thus suitable, for example, for thetreatment or prevention of diseases for which an inhibition ofangiogenesis and/or the VEGF receptor kinases is beneficial.

In one aspect of the invention, there is provide a nicotinamidepyridinurea compound of formula (I):

wherein:

-   A, E and Q independently of one another, are CH or N, whereby only a    maximum of two nitrogen atoms are contained in the ring; preferably    A, E, and Q are each CH;-   R¹ is aryl or heteroaryl, which may be optionally substituted in one    or more places in the same way or differently with halogen, hydroxy,    C₁-C₁₂-alkyl, C₃-C₆-cycloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,    aralkyloxy, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, ═O,    —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl    may be substituted with —OR⁵ or —NR⁷R⁸; preferably phenyl,    isoquinolyl, quinolinyl or indazolyl optionally substituted in one    or more places in the same way or differently with halogen, hydroxy,    C₁-C₁₂-alkyl, C₃-C₆-cycloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,    aralkyloxy, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, ═O,    —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl    may be substituted with —OR⁵ or —NR⁷R⁸; more preferably indazolyl    substituted in one or more places in the same way or differently    with halogen, hydroxy, C₁-C₁₂-alkyl, C₃-C₆-cycloalkyl,    C₂-C₆-alkenyl, C₂-C₆-alkynyl, aralkyloxy, C₁-C₁₂-alkoxy,    halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, ═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶,    —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may be substituted with —OR⁵    or —NR⁷R⁸; even more preferably indazolyl substituted with    C₁-C₁₂-alkyl; more preferably indazolyl substituted with —CH₃,    particularly 2-methyl-indazolyl;-   R², R³ and R⁹ independently of one another, are hydrogen or C₁-C₁₂    alkyl optionally substituted with halogen, —OR⁵, or C₁-C₁₂-alkoxy;    preferably hydrogen or unsubstituted C₁-C₁₂ alkyl; more preferably    hydrogen or —CH₃; or-   R⁹ is hydrogen, and-   R² and R³ together with the nitrogen atom to which they are attached    form a 3-8 membered heterocycloalkyl ring, preferably a 4-7 membered    heterocycloalkyl ring, which may optionally contain further    heteroatoms, such as nitrogen, oxygen or sulphur, and which may be    optionally substituted in one or more places in the same way or    differently with halogen, cyano, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,    halo-C₁-C₆-alkyl, ═O, —OR⁵, —SR⁴, —SOR⁴, —SO₂R⁶, —COR⁶, or —CO₂R⁶,    whereby C₁-C₁₂ alkyl optionally can also be substituted with a group    —OR⁵; preferably R² and R³ together with the nitrogen atom to which    they are attached form a 5 or 6 membered heterocycloalkyl ring,    which contains no or at least one further heteroatom, such as    nitrogen, oxygen or sulphur, and which may be optionally substituted    in one or more places in the same way or differently with halogen,    cyano, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —OR⁵,    —SR⁴, —SOR⁴, —SO₂R⁶, —COR⁶, or —CO₂R⁶, whereby C₁-C₁₂ alkyl    optionally can also be substituted with a group —OR⁵; or-   R³ is hydrogen or C₁-C₁₂-alkyl, whereby C₁-C₁₂ alkyl optionally can    also be substituted with a group —OR⁵; preferably is hydrogen or    CH₃; more particularly preferred hydrogen, and-   R² and R⁹ together with the two nitrogen atoms to which they are    attached form a 5-7 membered ring, preferably a 5 or 6 membered    ring, which may be optionally further substituted in one or more    places in the same way or differently with halogen, C₁-C₁₂-alkyl,    C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, or ═O, whereby C₁-C₁₂ alkyl    optionally can also be substituted with a group —OR⁵; preferably    together with the two nitrogen atoms to which they are attached form    a 5-7 membered saturated ring, preferably a 5 or 6 membered    saturated ring, which may be optionally further substituted in one    or more places in the same way or differently with halogen,    C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, or ═O, whereby C₁-C₁₂    alkyl optionally can also be substituted with a group —OR⁵; more    preferably together with the two nitrogen atoms to which they are    attached form a 5 membered saturated ring, optionally further    substituted in one or more places in the same way or differently    with halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, or ═O,    whereby C₁-C₁₂ alkyl optionally can also be substituted with a group    —OR⁵;-   R⁴ is C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, aryl or heteroaryl; preferably    C₁-C₁₂-alkyl; more preferably —CH₃;-   R⁵ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl or halo-C₁-C₆-alkyl;    preferably —CH₃ or hydrogen; more preferably hydrogen;-   R⁶ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl,    aryl, or —NR⁷R⁸; preferably C₁-C₁₂-alkyl or —NR⁷R⁸; more preferably    —CH₃;-   R⁷ and R⁸ independently of one another, are hydrogen, —SO₂R⁶, —COR⁶,    aryl, C₃-C₈-cycloalkyl, C₁-C₁₂-alkyl, halo-C₁-C₁₂-alkyl, or    C₁-C₁₂-alkoxy, whereby C₁-C₁₂-alkyl may be optionally substituted    with —OR⁵ or —N(CH₃)₂, or R⁷ and R⁸ may also be chosen in such a way    as to provide a 3-8 membered cycloalkyl ring, preferably a 4-7    membered cycloalkyl ring, more preferably a 5 or 6 membered ring,    which may optionally contain further heteroatoms, such as nitrogen,    oxygen or sulphur, and may be optionally substituted in one or more    places in the same way or differently with halogen, cyano,    C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —OR⁵, COR⁶, —SR⁴,    —SOR⁴ or —SO₂R⁶; preferably R⁷ and R⁸ independently of one another,    are hydrogen, COR⁶, —SO₂R⁶, C₁-C₁₂-alkyl; more preferably hydrogen    or C₁-C₁₂-alkyl; more preferably hydrogen or —CH₃,    and as well as isomers, diastereoisomers, enantiomers, tautomers and    salts thereof.

In a second aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof.

In a third aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof and atleast one pharmaceutically acceptable carrier, diluent or excipient.

In a fourth aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for usein the prevention or treatment of diseases associated with persistentangiogenesis and/or diseases associated with excessivelymphangiogenesis.

In a fifth aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for usein the prevention or treatment of tumor- or metastases-growth;psoriasis; Karposi's sarcoma; restenosis including stent-inducedrestenosis; Crohn's disease; Hodgkin's disease; leukemia; arthritisincluding rheumatoid arthritis, hemangioma, angiofibroma; endometriosis;eye diseases including diabetic retinopathy, neovascular glaucoma;corneal transplants; renal diseases, including glomerulonephritis,diabetic nephropathy, malignant nephrosclerosis, thromboticmicroangiopathic syndrome, transplant rejections and glomerulopathy;fibrotic diseases, including cirrhosis of the liver; mesangial cellproliferative diseases; arteriosclerosis; injuries to the nerve tissue,and for inhibiting the reocclusion of vessels after balloon cathetertreatment; in vascular prosthetics or after mechanical devices are usedto keep vessels open, as immunosuppresive agent for supporting scar-freehealing; senile keratosis; contact dermatitis; and asthma.

In a sixth aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for useas VEGF receptor kinase 3-inhibitors of lymphangiogenesis.

In a seventh aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for usein a method for the treatment of the human or animal body.

In a eighth aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for usein the preparation of a pharmaceutical product for the treatment of adisease for which an inhibition of angiogenesis and/or lymphangiogenesisand/or the VEGF receptor kinases is beneficial.

In a ninth aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for useas an inhibitor of the tyrosine kinases VEGFR-1 and VEGFR-2.

In a tenth aspect of the present invention, there is provided a compoundof general formula (III):

in which A, E, Q, R², R³ and R⁹, are as defined for formula (I) supraand R^(y) is H or C₁-C₆-alkyl, as an intermediate for the preparation ofa compound of formula (I) as defined supra. Preferably R¹ is H orC₁-C₂-alkyl; more preferably R^(y) is H or —CH₃.

In an eleventh aspect of the present invention, there is provided acompound of general formula (IIIA):

in which A, E, Q, W and are as defined for formula (I) supra, R^(Z) isC₁-C₁₂-alkyl and M is halogen, as an intermediate for the preparation ofa compound of formula (I) as defined supra. Preferably, M=a chlorineatom.

In a twelfth aspect of the present invention, there is provided the useof a compound of general formula (III), in which A, E, Q, R², R³ and R⁹are as defined for formula (I) supra and R^(y) is H or C₁-C₆-alkyl, orof a compound of general formula (IIIA), in which A, E, Q, M, and R¹ areas defined for formula (I) supra, as an intermediate for the preparationof a compound of formula (I), supra.

In a thirteenth aspect of the present invention, there is provided aprocess for the preparation of a compound of formula (I), wherein allsubstituents are as described in claim 1, in which a compound of formula(III), wherein A, E, Q, R², R³ and R⁹ are as defined in claim 1 andR^(y) is H or C₁-C₆-alkyl, is reacted with an amine of formula R¹NH₂ inwhich R¹ is as defined in claim 1.

In a fourteenth aspect of the present invention, there is provided aprocess for the preparation of a compound of formula (I), wherein allsubstituents are as described in claim 1, in which a compound of formula(II):

wherein A, E, Q, and R¹ are as defined in claim 1 and M stands forhalogen, is:

-   (i) first converted to an amine and subsequently converted to a    compound of formula (I) by reaction with a carbamoyl chloride of    formula ClCONR²R³, wherein R² and R³ are as defined in claim 1; or,    alternatively,-   (ii) reacted with a compound of formula R⁹HNCONR²R³, wherein R², R³    and R⁹ are as defined in claim 1, or, alternatively,-   (iii) first converted to an amine and subsequently converted to a    compound of formula (I) by first reacting with a compound of formula    ClCO₂Ph and then reacting with a compound of formula HNR²R³, wherein    R² and R³ are as defined in claim 1. Preferably a compound of    formula (I) is prepared using the (ii) process.

As used herein, the term “alkyl” is defined in each case as asubstituted or unsubstituted straight-chain or branched alkyl group,such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, decyl,undecyl, or dodecyl.

As used herein, the term “alkoxy” is defined in each case as astraight-chain or branched alkoxy group, such as, for example,methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,tert-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy,nonyloxy, decyloxy, undecyloxy or dodecyloxy.

As used herein, the term “cycloalkyl” is defined as a monocyclic alkylring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, and also as bicyclicrings or tricyclic rings, such as, for example, adamantanyl. Thecycloalkyl group may also contain, one or more heteroatoms, such asoxygen, sulphur and/or nitrogen, such that a heterocycloalkyl ring isformed.

As used herein, the term “heterocycloalkyl”, as used throughout thistext, e.g. as used in the definition of “R² and R³ together with thenitrogen atom to which they are attached form a 3-8 memberedheterocycloalkyl ring” is defined as a nitrogen atom-containingmonocyclic alkyl ring which optionally contains at least one furtherheteroatom, such as oxygen, sulphur and/or nitrogen, it being understoodthat said nitrogen atom links the heterocycloalkyl ring to the rest ofthe molecule. Preferred are 3-8 membered heterocycloalkyl rings, morepreferably 4-7 membered heterocycloalkyl rings. Even more preferred are5 or 6 membered heterocycloalkyl rings. For example, a heterocycloalkylring such as one selected from the following list can be mentioned:

It is understood that any of the above structures may contain at leastone additional heteroatom, such as nitrogen, oxygen or sulphur.

In particular, the following heterocycloalkyl rings can be mentioned:tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, morpholine,piperazine and thiomorpholine. The heterocycloalkyl ring may beoptionally substituted in one or more places in the same way ordifferently with, for example, halogen, cyano, C₁-C₁₂-alkyl,C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁶, —COR⁶,—CO₂R⁶, whereby C₁-C₁₂ alkyl optionally can also be substituted with agroup —OR⁵. It is understood that the substitution on any of theabove-mentioned heterocycloalkyl rings may take place on any one of theheterocycloalkyl ring's carbon atoms and/or on any one of theheterocycloalkyl ring's heteroatoms. Preferably the heterocycloalkylring is substituted in one or two places.

As used herein, the term “halogen” is defined in each case as fluorine,chlorine, bromine or iodine, with fluorine being preferred for compoundsof formula (I) and chlorine and bromine being preferred as substituent Min compounds of formula (II), (III), or (IIIA).

As used herein, the term “halo-C₁-C₆-alkyl” is defined as a C₁-C₆ alkylgroup wherein some or all hydrogen atoms are replaced by halogen atoms,preferably replaced by one or more fluoro atoms. Preferred is the groupCF₃.

As used herein, the term “alkenyl” is defined in each case as astraight-chain or branched alkenyl group that contains 2-6, preferably2-4 carbon atoms. For example, the following groups can be mentioned:vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl,but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl,2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, and allyl.

As used herein, the term “aryl” is defined in each case as having 3-12carbon atoms, preferably 6-12 carbon atoms, such as, for example,cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl,indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl etc,phenyl being preferred.

As used herein, the term “C₁-C₁₂”, as used throughout this text e.g. inthe context of the definitions of “C₁-C₁₂-alkyl” and “C₁-C₁₂-alkoxy”, isto be understood as meaning an alkyl or alkoxy group having a finitenumber of carbon atoms of 1 to 12, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 carbon atoms. It is to be understood further that said term“C₁-C₁₂” is to be interpreted as any subrange comprised therein, e.g.C₁-C₁₂, C₂-C₁₁, C₃-C₁₀, C₄-C₉, C₅-C₈, C₆-C₇, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅,C₁-C₆, C₁-C₇, C₁-C₈, C₁-C₉, C₁-C₁₀, C₁-C₁₁; preferably C₁-C₂, C₁-C₃,C₁-C₄, C₁-C₅, C₁-C₆; more preferably C₁-C₃.

Similarly, as used herein, the term “C₂-C₆”, as used throughout thistext e.g. in the context of the definitions of “C₂-C₆-alkenyl”, is to beunderstood as meaning an alkenyl group having a finite number of carbonatoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to beunderstood further that said term “C₂-C₆” is to be interpreted as anysubrange comprised therein, e.g. C₂-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄,C₂-C₅; preferably C₂-C₃.

Further as used herein, the term “C₁-C₆”, as used throughout this texte.g. in the context of the definitions of “halo-C₁-C₆-alkyl”, is to beunderstood as meaning a haloalkyl group having a finite number of carbonatoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to beunderstood further that said term “C₁-C₆” is to be interpreted as anysubrange comprised therein, e.g. C₁-C₆, C₂-C₅, C₃-C₄, C₁-C₂, C₁-C₃,C₁-C₄, C₁-C₅, C₁-C₆; more preferably C₁-C₃.

As used herein, the term “heteroaryl” as defined in each case, is anaromatic ring system which contains, in the ring, at least oneheteroatom which contains at least one heteroatom which may be identicalor different, and which comprises 3-16 ring atoms, preferably 5 or 6 or9 or 10 atoms, said heteroatom being such as oxygen, nitrogen orsulphur, and can be monocyclic, bicyclic, or tricyclic, and in additionin each case can be benzocondensed. Preferably, heteroaryl is selectedfrom thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, etc., and benzo derivatives thereof, such as, e.g.,benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl,benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzoderivatives thereof, such as, e.g., quinolinyl, isoquinolinyl, etc.; orazocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; orcinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, xanthenyl, or oxepinyl, etc. More preferably theheteroaryl is selected from quinolinyl, isoquinolinyl, or indazolyl.More preferably still, the heteroaryl is indazolyl.

The aryl group and the heteroaryl group in each case can be substitutedin the same way or differently in one or more places with halogen,hydroxy, C₁-C₁₂-alkyl, C₂-C₆-alkenyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl,═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkylmay be substituted with —NR⁷R⁸. It is understood that the substitutionon the aryl group and the heteroaryl group may take place on any one ofthe group's carbon atoms and/or on any one of the heteroatoms.Preferably the aryl group and the heteroaryl group is substituted in oneor two places.

If an acid group is included, the physiologically compatible salts oforganic and inorganic bases are suitable as salts, such as, for example,the readily soluble alkali salts and alkaline-earth salts as well asN-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine,1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and1-amino-2,3,4-butanetriol.

If a basic group is included, the physiologically compatible salts oforganic and inorganic acids are suitable, such as hydrochloric acid,sulphuric acid, phosphoric acid, citric acid, tartaric acid, succinicacid, fumaric acid.

The compounds of general formula (I) according to the invention alsocontain the possible tautomeric forms and comprise the E-isomers orZ-isomers, or, if one or more stereogenic centers are present, racematesand/or enantiomers and/or diastereoisomers. Thus, a molecule with asingle stereogenic center may be a mixture of enantiomers (R,S), or maybe a single (R) or (S) enantiomer. A molecule with more than onestereogenic center may be a mixture of diastereoisomers, or may be asingle diastereoisomer, whereby the diastereoisomers may also exist asmixtures of enantiomers or single enantiomers.

One embodiment of the present invention are compounds of formula (I)wherein A, E, and Q are each CH.

In one embodiment, R¹ is aryl or heteroaryl, which may be optionallysubstituted in one or more places in the same way or differently withhalogen, hydroxy, C₁-C₁₂-alkyl, C₃-C₆-cycloalkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, aralkyloxy, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl,cyano-C₁-C₆-alkyl, ═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸,whereby C₁-C₁₂-alkyl may be substituted with —OR or —NR⁷R⁸. In anotherembodiment, R¹ is phenyl, isoquinolinyl, quinolinyl or indazolyloptionally substituted in one or more places in the same way ordifferently with halogen, hydroxy, C₁-C₁₂-alkyl, C₃-C₆-cycloalkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, aralkyloxy, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, ═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶,—CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may be substituted with —OR⁵ or—NR⁷R⁸. In a preferred embodiment, R¹ is indazolyl substituted in one ormore places in the same way or differently with halogen, hydroxy,C₁-C₁₂-alkyl, C₃-C₆-cycloalkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,aralkyloxy, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, cyano-C₁-C₆-alkyl, ═O,—SO₂R⁶, —OR⁵, —SOR⁴, —COR, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may besubstituted with —OR⁵ or —NR⁷R⁸. In a more preferred embodiment, R¹ isindazolyl substituted with C₁-C₁₂-alkyl, optionally having a halogenatom substituent, preferably a fluorine, chlorine, bromine, or iodineatom. In an even more preferred embodiment, R¹ is indazolyl substitutedwith —CH₃. In an even more particularly preferred embodiment, R¹ is2-methyl-indazolyl.

In one embodiment, R², R³ and R⁹ independently of one another, arehydrogen or C₁-C₁₂ alkyl optionally substituted with halogen, —OR⁵, orC₁-C₁₂-alkoxy. In a preferred embodiment R², R³ and R⁹ independently ofone another, are hydrogen or C₁-C₁₂ alkyl. In a more preferredembodiment R² and R³ independently of one another are hydrogen or —CH₃and R⁹ is hydrogen.

In another embodiment, R⁹ is hydrogen and R² and R³ together with thenitrogen atom to which they are attached form a 3-8 memberedheterocycloalkyl ring, preferably a 4-7 membered heterocycloalkyl ring,which may optionally contain further heteroatoms, such as nitrogen,oxygen or sulphur, and which may be optionally substituted in one ormore places in the same way or differently with halogen, cyano,C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —OR⁵, —SR⁴, —SOR⁴,—SO₂R⁶, —COR⁶, or —CO₂R⁶, whereby C₁-C₁₂ alkyl optionally can also besubstituted with a group —OR⁵. In a preferred embodiment, R⁹ is hydrogenand R² and R³ together with the nitrogen atom to which they are attachedform a 5 or 6 membered heterocycloalkyl ring, which contains no or atleast one further heteroatom, such as nitrogen, oxygen or sulphur, andwhich may be optionally substituted in one or more places in the sameway or differently with halogen, cyano, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, ═O, —OR⁵, —SR⁴, —SOR⁴, —SO₂R⁶, —COR⁶, or —CO₂R⁶,whereby C₁-C₁₂ alkyl optionally can also be substituted with a group—OR⁵.

In another embodiment, R³ is hydrogen or C₁-C₁₂-alkyl, whereby C₁-C₁₂alkyl optionally can also be substituted with a group —OR⁵ and R² and R⁹together with the two nitrogen atoms to which they are attached form a5-7 membered ring, preferably a 5 or 6 membered ring, which may beoptionally further substituted in one or more places in the same way ordifferently with halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl,or ═O, whereby C₁-C₁₂ alkyl optionally can also be substituted with agroup —OR⁵. In a preferred embodiment, R³ is hydrogen or —CH₃ and R² andR⁹ together with the two nitrogen atoms to which they are attached forma 5-7 membered saturated ring, preferably a 5 or 6 membered saturatedring, which may be optionally further substituted in one or more placesin the same way or differently with halogen, C₁-C₁₂-alkyl,C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, or ═O, whereby C₁-C₁₂ alkyl optionallycan also be substituted with a group —OR⁵. In a more preferredembodiment, R³ is hydrogen and R² and R⁹ together with the two nitrogenatoms to which they are attached form a 5 membered saturated ringoptionally further substituted in one or more places in the same way ordifferently with halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl,or ═O, whereby C₁-C₁₂ alkyl optionally can also be substituted with agroup —OR⁵.

In one embodiment, R⁴ is C₁-C₁₂-alkyl. In a preferred embodiment, R⁴ is—CH₃.

In one embodiment, R⁵ is —CH₃ or hydrogen. In a preferred embodiment, R⁵is hydrogen.

In one embodiment, R⁶ is C₁-C₁₂-alkyl or —NR⁷R⁸. In a preferredembodiment, R⁶ is C₁-C₁₂-alkyl. In a more preferred embodiment, R⁶ is—CH₃.

In one embodiment, R⁷ and R⁸ independently of one another, are hydrogen,COR⁶, SO₂R⁶, C₁-C₁₂-alkyl. In a preferred embodiment, R⁷ and R⁸independently of one another are hydrogen or —CH₃.

Some specific examples of compounds of the present invention include thefollowing:

-   N-(2-methyl-2H-indazol-6-yl)-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinamide,-   2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide,-   N-(1-methyl-1H-indazol-6-yl)-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinamide,-   N-isoquinolin-3-yl-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinamide,-   N-(1-methyl-1H-indazol-5-yl)-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinamide,-   morpholine-4-carboxylic acid    (4-{[3-(2-methyl-2H-indazol-6-ylcarbamoylpyridin-2ylamino]-methyl}-pyridin-2-yl)-amide,-   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-nicotinamide,-   N-(2-methyl-2H-indazol-6-yl)-2-({2-[3-(1-methyl-piperidin-4-yl)-ureido]-pyridin-4-ylmethyl}-amino)-nicotinamide,    and-   N-(2-methyl-2H-indazol-6-yl)-2-{[2-(2-oxo-imidazolidin-1-yl)-pyridin-4-ylmethyl]-aminoo}-nicotinamide;    as well as isomers, diastereoisomers, enantiomers, tautomers and    salts thereof.

The compounds of formula (I) can be used as pharmaceutical agents basedon their inhibitory activity relative to the phosphorylation of VEGFreceptors. Based on their profile of action, the compounds according tothe invention are suitable for preventing or treating diseases that arecaused or promoted by persistent angiogenesis.

Since the compounds of formula (I) are identified as inhibitors of thetyrosine kinases VEGFR-1 and VEGFR-2, they are suitable in particularfor preventing or treating those diseases that are caused or promoted bypersistent angiogenesis that is triggered via the VEGF receptor or by anincrease in vascular permeability.

The present invention also provides the use of the compounds of formula(I) as inhibitors of the tyrosine kinases VEGFR-1 and VEGFR-2, or KDRand FLT.

The term “diseases that are caused or promoted by persistentangiogenesis” relates especially to diseases such as tumor or metastasisgrowth, psoriasis, Kaposi's sarcoma, restenosis, such as, e.g.,stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin'sdisease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma,angiofibroma; eye diseases, such as diabetic retinopathy, neovascularglaucoma; corneal transplants; renal diseases, such asglomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,thrombic microangiopathic syndrome, transplant rejections andglomerulopathy; fibrotic diseases, such as cirrhosis of the liver,mesangial cell proliferative diseases, arteriosclerosis, injuries tonerve tissue, and for inhibiting the reocclusion of vessels afterballoon catheter treatment, in vascular prosthetics or after mechanicaldevices are used to keep vessels open, such as, e.g., stents, asimmunosuppressive agents, for supporting scar-free healing, in senilekeratosis, in contact dermatitis, and in asthma.

In treating injuries to nerve tissue, quick scar formation on the injurysites can be prevented with the compounds according to the invention,i.e., scar formation is prevented from occurring before the axonsreconnect. A reconstruction of the nerve compounds can be thusfacilitated.

The formation of ascites in patients, especially patients suffering fromtumors caused by metastases, can also be suppressed with the compoundsaccording to the invention. VEGF-induced oedemas can also be suppressed.

By a treatment with the compounds of formula (I), not only a reductionof the size of metastases but also a reduction of the number ofmetastases can be achieved.

Lymphangiogenesis plays an important role in lymphogenic metastasis(Karpanen, T. et al., Cancer Res. 2001 Mar. 1, 61(5): 1786-90, Veikkola,T., et al., EMBO J. 2001, Mar. 15; 20 (6): 1223-31).

The compounds of formula (I) also show excellent action as VEGFR kinase3 inhibitors and are, therefore, also suitable as effective inhibitorsof lymphangiogenesis.

The compounds of formula (I) are thus effective in the prevention ortreatment of diseases that are associated with excessivelymphangiogenesis, such as lymphedema, lymphangiectasia, lymphangioma,and lymphangiosarcoma but also asthma. Lymphatic growth around tumorsmay facilitate metastatic spread of malignant cells that ultimately killthe patient. This process can be effectively hindered by the compoundsof this invention. Thus the compounds are not only effective ininhibiting metastasis growth, but can also be effective in reducing thenumber of metastases.

This invention also provides the use of the compounds of formula (I) asinhibitors of the tyrosine kinase VEGFR-3 (FLT-4).

A further object of this invention is also a pharmaceutical agent forpreventing or treating diseases that are associated with excessivelymphangiogenesis, such as metastasis growth, lymphedema,lymphangiectasia, lymphangioma, and lymphangiosarcoma but also asthma.

Furthermore, the invention relates to the use of the compounds ofgeneral formula (1) for the preparation of a pharmaceutical agent foruse in or for the prevention or treatment of tumor or metastasis growth,psoriasis, Kaposi's sarcoma, restenosis, such as, e.g., stent-inducedrestenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia;arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; eyediseases, such as diabetic retinopathy, neovascular glaucoma; cornealtransplants; renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombic microangiopathicsyndrome, transplant rejections and glomerulopathy; fibrotic diseases,such as cirrhosis of the liver, mesangial cell proliferative diseases,arteriosclerosis, injuries to nerve tissue, and for inhibiting thereocclusion of vessels after balloon catheter treatment, in vascularprosthetics or after mechanical devices are used to keep vessels open,such as, e.g., stents, as immunosuppressive agents, for supportingscar-free healing, in senile keratosis, in contact dermatitis, and alsoin asthma.

To use the compounds of formula (I) as pharmaceutical agents, the latterare brought into the form of a pharmaceutical preparation, which inaddition to the active ingredient for enteral or parenteraladministration contains suitable pharmaceutical, organic or inorganicinert carrier materials, such as, for example, water, gelatin, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The pharmaceutical preparations can bepresent in solid form, for example as tablets, coated tablets,suppositories, capsules or in liquid form, for example as solutions,suspensions or emulsions. They also can contain, moreover, adjuvantssuch as preservatives, stabilizers, wetting agents or emulsifiers, saltsfor changing osmotic pressure or buffers.

For parenteral administration, especially injection solutions orsuspensions, especially aqueous solutions of the active compounds inpolyhydroxyethoxylated castor oil, are suitable.

As carrier systems, surface-active adjuvants such as salts of bile acidsor animal or plant phospholipids, but also mixtures thereof as well asliposomes or components thereof can also be used.

For oral administration, especially tablets, coated tablets or capsuleswith talc and/or hydrocarbon vehicles or binders, such as for example,lactose, corn starch or potato starch, are suitable. The administrationcan also be carried out in liquid form, such as, for example, as juice,to which optionally a sweetener or, if necessary, one or more flavouringsubstances, is added.

The dosage of the active ingredients can vary depending on the method ofadministration, age and weight of the patient, type and severity of thedisease to be treated and similar factors. The daily dose is 0.5-1000mg, preferably 50-200 mg, whereby the dose can be given as a single doseto be administered once or divided into 2 or more daily doses.

A further object of this invention is therefore a pharmaceutical agentcomprising a compound of formula (I) in combination with at least onepharmaceutically acceptable carrier or excipient.

Compounds of formula (I) are obtained, in that a compound of generalformula (II):

in which A, E, Q, and R¹ are defined supra as for general formula (I)and M stands for halogen, is (i) first converted to an amine and then,by reaction with a carbamoyl chloride of formula ClCONR²R³ in which R²and R³ are defined supra as for general formula (I), is converted to aurea of general formula (I), or (ii) reacted with a urea of generalformula R⁹HNCONR²R³ in which R², R³ and R⁹ are defined supra as forgeneral formula (I), or (iii) first converted to an amine, thenconverted to a compound of formula (I) by first reacting with a compoundof formula ClCO₂Ph and then reacting with a compound of formula HNR²R³,wherein R² and R³ are defined supra as for general formula (I); or acompound of general formula (III) in which A, E, Q, R², R³ and R⁹ aredefined as for general formula (1) and R^(y) stands for H orC₁-C₆-alkyl, is reacted with an amine of general formula R¹NH₂ in whichR¹ is defined supra as for general formula (I):

There are many methods known to the person skilled in the art in theliterature for amide formation. For example, it is possible to startfrom the corresponding ester. The ester may be reacted according to J.Org. Chem. 1995, 8414 with trimethylaluminium and the correspondingamine in solvents such as toluene, at temperatures of 0° C. to theboiling point of the solvent. If the molecule contains two ester groups,both are converted into the same amide. Instead of trimethylaluminium,sodium hexamethyldisilazide can also be used.

For amide formation, however, all processes that are known to the personskilled in the art from peptide chemistry are also available. Forexample, the corresponding acid, obtained from the corresponding esterby saponification, can be reacted with the amine in aprotic polarsolvents, such as, for example, dimethylformamide, via an activated acidderivative, obtainable, for example, with hydroxybenzotriazole and acarbodiimide, such as, for example, diisopropylcarbodiimide, attemperatures of between 0° C. and the boiling point of the solvent,preferably at 80° C., or else with preformed reagents, such as, forexample, HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (Chem. Comm. 1994, 201), at temperatures of between0° C. and the boiling point of the solvent, preferably at roomtemperature. The addition of a base such as N-methylmorpholine, forexample, is necessary. Amide formation, may also be accomplished via theacid halide, mixed acid anhydride, imidazolide or azide.

The ureas of aryl- or heteroaryl amines may be prepared by a variety ofliterature known methods, known to the person skilled in the art. Forexample, they may be prepared by the reaction of aryl- or heteroarylamines with isocyanates, the reaction of amines with aryl- orheteroaryl-carbamates such as aryl- or heteroaryl-phenoxycarbamates, orthe reaction of aryl- or heteroaryl amines with appropriatelysubstituted carbamoyl chlorides, or the reaction of an aryl- orheteroaryl-halide with ureas under the influence of metal catalysis.

For example, the ureas of aminopyridines may be prepared by reacting aurea with halopyridines, whereby chloro and bromopyridines arepreferred, under the catalytic influence of metal complexes, forexample, palladium- or copper complexes. In the case of copper complexesthe use of stoichiometric amounts of the copper complexes may beadvantageous for the reaction outcome. Suitable copper salts for thereaction are copper (I) or copper (II) salts whereby copper (I) saltssuch as, for example, copper (I) oxide or copper (I) iodide, arepreferred. In the case of copper (I) iodide the addition of an additivesuch as, for example, ethylenediamine is necessary. Suitable solventsfor this copper-promoted coupling are dioxane or dimethylformamide, attemperatures upto the boiling point of the solvents, whereby 120° C. ispreferred. Addition of a base is also necessary, such as potassiumphosphate or cesium carbonate. In the case of palladium catalysis,palladium complexes such as tris-(dibenzylideneacetone)-dipalladium(0)maybe employed. Suitable solvents for the reaction are toluene, dioxaneor dimethylformamide, whereby mixtures of solvents may also beadvantageous for the reaction, at temperatures from room temperature tothe boiling points of the solvents, whereby 110° C. is preferred. Aco-ligand such as BINAP, DPPF or xantphos is also employed. A base isalso required, suitable bases for the reaction are for example, cesiumcarbonate, potassium phosphate or sodium tert-butoxide.

The required urea starting materials for the above copper or palladiumpromoted coupling may in turn be prepared from the reaction of thecorresponding amines with the corresponding isocyanates. Solvents suchas for example dichloromethane, or isopropylalcohol may be employed attemperatures from 0° C. to the boiling points of the solvents, wherebyroom temperature is preferred.

The required 2-amino-nicotinic acid esters (general formula II,Scheme 1) may be prepared by a variety of methods. For example, known2-chloronicotinic acid esters may be reacted with appropriatelysubstituted amines at elevated temperatures whereby 120° C. ispreferred. The reaction may be conducted without solvents. In turn, theamines may be obtained from the corresponding nitrites, for example, byhydrogenation in the presence of a suitable metal catalyst, such asRaney Nickel. Alternatively, the nitrile may be reduced with metalhydride reagents such as, for example, lithium aluminium hydride.Similar reductions of aryl nitrites to benzylamines are well documentedin the literature and are well known to the person skilled in the art.An alternative preparation of the required 2-amino-nicotinic acid estersis accomplished as outlined in Scheme 1, in which A, E, Q, R¹, R², R³,and R⁹ are defined in the same way as for the general formula (I), M ishalogen and R^(y) is H or C₁-C₆-alkyl. Esterification of2-aminonicotinic acid may be accomplished by a variety of well knowntechniques, well known to the person skilled in the art. Acylation withan appropriately substituted activated acid derivative, for example, thecorresponding acid halides or anhydrides, whereby the acid chloride ispreferred, in inert solvents, for example, dichloromethane, withaddition of tertiary amine bases, for example triethylamine, withcooling, whereby cooling at 0° C. is preferred, delivers thecorresponding amide derivatives. The amides may be reduced to compoundsof general formula (II) by employing a suitable reducing agent, forexample a borane complex such as borane-dimethyl sulphide complex, insolvents, for example, tetrahydofuran, at temperatures ranging fromchilled to room temperature to the boiling point of the solvents,whereby room temperature is preferred.

Methods for the preparation of substituted or unsubstituted6-aminoindazoles are well known to the person skilled in the art, in theliterature. They may be obtained from the reduction of the correspondingnitroindazoles via catalytic hydrogenation or other reduction methodswell known to the person skilled in the art. N-alkylation of substitutednitroindazoles may be accomplished with a variety of literature-knownalkylating agents. For example, methylation of N−1 or N-2 of a suitablyfunctionalised 6-nitroindazole may be accomplished by for exampletreatment with a base, preferably Cs₂CO₃ or NaH, and a methyl halide,preferably methyl iodide in a suitable solvent such asN,N-dimethylformamide, at temperatures ranging from 0° C. to 50° C.,whereby 50° C. is preferred. 3-Substituted-6-nitroindazoles may beprepared by a variety of methods. For example alkyl substituents may beintroduced in the 3-position by way of standard Suzuki reactions betweenan appropriate 3-haloindazole, whereby the appropriate 3-iodoindazolesare preferred, and an alkyl boronic acid, whereby the trialkylboraxinesmay also be employed. N-protection of the indazole may be advantageousfor the reaction. 6-Nitroindazole-3-carboxylic acid provides a suitablestarting material for ester, amide, hydroxymethyl and alkoxymethylsubstitution in the 3-position of 6-nitroindazole, via transformationswell known to the person skilled in the art, such astransesterification, amide coupling, reduction, or reduction followed byalkylation. 6-Nitroindazole-3-carbaldehyde (prepared by the reaction ofcommercial 6-nitroindole with NaNO₂ in the presence of dilute aqueoushydrochloric acid according to J. Med. Chem. 2001, 44, 7, 1021) providesa useful precursor to 6-nitroindazole-3-carboxylic acid via well knownoxidation methods. In turn 6-nitroindazole-3-carbaldehyde may also beconverted to 3-hydroxymethyl-6-nitroindazole,3-alkoxymethyl-6-nitroindazole, or 3-aminomethyl-6-nitroindazolederivatives by equally standard transformations such as reduction,reduction followed by alkylation, or reductive amination. Such standardtransformations may also be applied to the synthesis of othersubstituted aminoindazoles. A variety of substituted nitroindazoles arecommercially available, however they may be readily synthesised via thereaction of a suitable 2-amino-nitrotoluene derivative with, forexample, NaNO₂ and aqueous hydrochloric acid. If required, the nitrogroup may be introduced after the cyclisation reaction of a suitable2-aminotoluene derivative by standard nitration chemistry.

The preparation of N-alkylated-aminobenzimidazoles may be accomplishedfrom the corresponding N-alkylated-nitrobenzimidazoles via standardreduction chemistry. Alkylation of a suitable functionalisednitrobenzimidazole, for example with an alkyl halide and a base,furnishes N1- and N3-alkylated-nitrobenzimidazoles, which may beseparated and isolated in pure form by standard purification techniques.For example, 6-amino-1-methyl-benzimidazole may be produced by thereaction of commercial 5-nitrobenzimidazole with MeI and Cs₂CO₃ in DMFfollowed by purification (of the resulting mixture of 5- and6-nitro-1-methyl-benzimidazoles) and hydrogenation in the presence of10% Pd on charcoal. Similarly, the preparation ofN-alkylated-aminobenzotriazoles may also be accomplished from thecorresponding nitrobenzotriazoles. Alkylation of a suitablefunctionalised nitrobenzotriazole, for example with an alkyl halide anda base, furnishes N1-, N2- and N3-alkylated-nitrobenzotriazoles, whichmay be separated and isolated in pure form by standard purificationtechniques. Standard reduction chemistry furnishes the correspondingaminobenzotriazoles. For example, 5-amino-2-methyl-benzotriazole may beprepared according to a literature procedure (Eur. J. Med. Chem. 1992,27, 161-166).

The preparation of 3-aminoisoquinolines which are substituted in the7-position, may be accomplished via the corresponding3-amino-1-bromo-7-substituted isoquinoline by way of reductivedehalogenation. 3-amino-1-bromo-7-substituted isoquinolines may in turnbe prepared by the reaction of a suitable2-cyano-4-substituted-benzeneacetonitrile with HBr in acetic acid. Forexample, 3-amino-7-methoxyisoquinoline may be prepared in two steps (HBrmediated cyclisation followed by reductive dehalogenation) from2-cyano-4-methoxy-benzeneacetonitrile, which may be prepared accordingto a literature procedure (Bull. Chem. Soc. Jpn. 1980, 53, 10,2885-2890).

1-Alkyl-6-amino-quinolin-2-ones may be prepared by methods known to theperson skilled in the art. For example, 6-amino-2-methyl-quinolin-2-onemay be prepared according to a literature procedure (J. Chem. Research,Synopses, 1997, 310-311).

2-Amino-3,6-disubstituted quinolines may be prepared by a number ofprocedures. For example, the reaction of the lithium salt (generatedwith a base such as lithium diisopropylamide) of a suitably substitutedcyanomethyl-dialkylphosphonate with a suitably substituted2-nitrobenzaldehyde derivative in a suitable solvent, such as THF,furnishes a suitable acrylonitrile derivative which may be cyclised tothe desired 2-amino-3,6-disubstituted quinoline by treating with asuitable reducing agent, such as iron in acetic acid.

The compounds of the general formulae II, III, and IIIA:

in which A, E, Q, R¹, R², R³, and R⁹ are defined in the same way as forthe general formula (I), R^(Z) is C₁-C₁₂-alkyl, M is halogen and Re is Hor C₁-C₆-alkyl, provide valuable intermediates for the preparation ofthe inventive compounds of general formula (I) and, are therefore alsoobjects of the invention. The use of compounds of formula (II) and (III)in the production of a compound of formula (I), as well as the processdescribed above using these compounds in the production of a compound offormula (I) are also objects of the invention.

EXAMPLES

Production of the Compounds According to the Invention

The following examples explain the production of the compounds accordingto the invention without the scope of the claimed compounds beinglimited to these examples.

Abbreviations

The following abbreviations used in the invention have the followingmeanings:

-   Brine saturated aqueous sodium chloride solution-   CI+ chemical ionisation (NH₃)-   DCE 1,2-dichloroethane-   DMF N,N-dimethyl formamide-   d₆-DMSO d₆-dimethylsulphoxide-   d doublet-   dd doublet of doublets-   ES+ positive mode electrospray ionisation-   EtOAc ethyl acetate-   EtOH ethanol-   1H-NMR proton nuclear magnetic resonance spectroscopy: chemical    shifts (δ) are given in ppm.-   Hex n-hexane-   LC-ES+ liquid chromatography/positive mode electrospray ionisation-   LDA Lithium diisopropylamide-   MeOH methanol-   m multiplet-   Mp. melting point-   MS mass spectrometry-   m/z mass/charge ratio-   Pd₂dba₃ tris-(dibenzylideneacetone)-dipalladium(0)-chloroform    complex-   rt room temperature-   RT retention time (LC)-   s singlet-   THF tetrahydrofuran-   t triplet-   Xantphos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene

Example 1.0 Preparation ofN-(2-methyl-2H-indazol-6-yl)-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinamide

A suspension of 2-methyl-2H-indazol-6-ylamine [Davies J. Chem. Soc.;1955; 2412-2419] (809 mg, 5.5 mmol) in DCE (13.5 mL) was treated at 0°C. consecutively with, trimethylaluminium (2 M) in toluene (4.23 mL,8.46 mmol), 2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinicacid methyl ester (1.34 g, 4.23 mmol) and DCE (20 mL). The reactionmixture was placed under a nitrogen atmosphere and heated for 10 hoursat 85° C. (bath temperature). On cooling the reaction was poured intoaqueous sodium-potassium tartrate solution (150 mL) and partitionedbetween EtOAc and water. The organic phase was washed with brine, dried,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel (Gradient elution: 100% CH₂Cl₂ to 90%CH₂Cl₂/10% MeOH) to giveN-(2-methyl-2H-indazol-6-yl)-2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinamide(964 mg, 53%) as a solid; Mp. 205-207° C.

The following examples were prepared in analogy to Example 1 from2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinic acid methylester and the corresponding amine:

Example Nr. R¹ MW Mp. [° C.] 1.1

444.42 206-207 1.2

430.47 228-229 1.3

427.47 191-192 1.4

430.47 219-220

Example 2.0 Preparation of morpholine-4-carboxylic acid(4-{[3-(2-methyl-2H-indazol-6-ylcarbamoyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amide

A mixture of2-[(2-chloro-pyridin-4-ylmethylpamino]-N-(2-methyl-2H-indazol-6-yl)-nicotinamide(200 mg, 0.51 mmol), Pd₂ dba₃ (5.2 mg, 0.0051 mmol), xantphos (9.1 mg,0.0153 mmol), cesium carbonate (169 mg, 0.54 mmol) andmorpholine-4-carboxylic acid amide (332 mg, 2.55 mmol) in dioxane (12.1mL) and DMF (4.1 mL) under nitrogen, was stirred at 110° C. for 11hours. A second reaction was performed in duplicate. The two reactionswere combined, diluted with dilute aqueous sodium hydrogencarbonatesolution and extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated in vacuo. Purification wasachieved by chromatography on Isolute® flash silica gel (Separtis) togive morpholine-4-carboxylic acid(4-{[3-(2-methyl-2H-indazol-6-ylcarbamoylipyridin-2-ylamino]-methyl}-pyridin-2-yl)-amide(119 mg) which was further purified by recrystallisation from EtOAc;1H-NMR (300 MHz, d₆-DMSO) 10.2 (1H, s), 9.06 (1H, s), 8.45 (1H, t), 8.22(1H, s), 8.03-8.13 (4H, m), 7.73 (1H, s), 7.62 (1H, d), 7.27 (1H,unresolved dd), 6.89 (1H, unresolved dd), 6.67 (1H, dd), 4.62 (2H, d),4.10 (3H, s), 3.52 (4H, t), 3.39 (4H, t).

The following examples were prepared in analogy to Example 2.0 from thecorresponding 2-chloropyridine derivative and the corresponding urea:Example Nr. Structure MW H-NMR (d₆-DMSO) 2.1

444.50 δ (600 MHz) 10.25 (1H, s), 8.74 (1H, s), 8.48 (1H, t), 8.27 (1H,s), 8.15-8.17 (1H, m), 8.08-8.13 (3H, m), 7.77 (1H, s), 7.65 (1H, d),7.29 (1H, d), 6.90 (1H, d), 6.69 (1H, dd), 4.65 (2H, d), 4.14 (3H, s),2.91 (6H, s). 2.2

513.60 δ (600 MHz) 10.22 (1H, s), 9.06 (1H, s), 8.50 (1H, t), 8.25 (1H,s), 8.05-8.17 (4H, m), 7.65 (1H, d), 7.37-7.40 (1H, m), 7.27-7.31 (1H,m), 6.85 (1H, d), 6.69 (1H, dd), 4.62 (2H, d), 4.13 (3H, s), 3.49-3.57(1H, m), 2.58-2.65 (2H, m), 2.17 (3H, s), 2.02-2.11 (2H, m), 1.78-1.83(2H, m), 1.37-1.46 (2H, m). 2.3

442.48 δ (300 MHz) 10.23 (1H, s), 8.49 (1H t), 8.27 (1H, s), 8.09-8.19(5H, m), 7.65 (1H, d), 7.30 (1H, unresolved dd), 7.11 (1H, s), 6.92 (1H,d), 6.69 (1H, dd), 4.65 (2H, d), 4.12 (3H, s), 3.97 (2H, t), 3.38 (2H,t).Production of Starting and Intermediate Compounds

If the production of the intermediate compounds is not described, thelatter are known or can be produced analogously to known compounds orprocesses that are described here or in WO2004/013102.

Example 3.1 Preparation of 1-(4-cyano-pyridin-2-yl)-3-methyl-urea

A mixture of 2-chloro-isonicotinonitrile [Talik et al. Rocz. Chem.; 29;1955; 1019, 1025.] (13.9 g, 0.1 mol), Pd₂ dba₃ (2.0 g, 2 mmol), Xantphos(3.6 g, 6.22 mmol), cesium carbonate (39.1 g, 120 mmol) and methylurea(37.04 g, 0.5 mol) in dioxane (800 mL), under a nitrogen atmosphere washeated for 8 hours at 130° C. (bath temperature). On cooling thereaction mixture was concentrated in vacuo. The residue was partitionedbetween CH₂Cl₂ and water. The organic phase was washed with brine,dried, filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel (gradient elution: 100% hexane to 100%EtOAc) to give 1-(4-cyano-pyridin-2-yl)-3-methyl-urea (12.1 g) as asolid; Mp. 203-204° C.

Example 3.2 Preparation of 1-(4-aminomethyl-pyridin-2-yl)-3-methyl-urea

A solution of 1-(4-cyano-pyridin-2-yl)-3-methyl-urea (12.0 g, 11.4 mmol)in THF (80 mL) was treated with Raney nickel (0.5 g) placed under ahydrogen atmosphere (atmospheric pressure) for 8 hours at rt. Thereaction mixture was diluted with EtOAc, filtered over Celite® andconcentrated in vacuo. The residue was purified by chromatography onsilica gel (Gradient elution: 100% CH₂Cl₂ to 85%/15% CH₂Cl₂/MeOH) togive 1-(4-aminomethyl-pyridin-2-yl)-3-methyl-urea (4.8 g) as a solid.

Example 3.3 Preparation of2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinic acid methylester

A mixture of 1-(4-aminomethyl-pyridin-2-yl)-3-methyl-urea (3.8 g, 21.1mmol) and 2-chloro-nicotinic acid methyl ester [Mann et al. J. Chem.Soc.; 1952; 2057, 2060] (1.78 g, 10.4 mmol) was heated for 1 hour at120° C. The crude product was purified by chromatography on silica gel(Gradient elution: 100% CH₂Cl₂ to 93% CH₂Cl₂/7% MeOH) to give2-{[2-(3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-nicotinic acid methylester (2.06 g); Mp. 145-146° C.

Example 4.1 Preparation of 2-amino-nicotinic acid methyl ester

A stirred suspension of 2-amino-nicotinic acid (12.15 g, 87.95 mmol) ina mixture of MeOH (175 mL) and THF (500 mL), under nitrogen at roomtemperature, was added a solution of trimethylsilyldiazomethane (2M inhexane, 50 mL, 99.5 mmol)) dropwise. After completion of the reactionthe volatiles were removed in vacuo and the crude product trituratedwith disisopropyl ether, filtered and dried to give 2-amino-nicotinicacid methyl ester (10.44 g) as a yellow solid.

Example 4.2 Preparation of 2-chloro-isonicotinoyl chloride

A mixture of 2-chloro-isonicotinic acid (15 g, 95.2 mmol) and thionylchloride (90 mL) was heated at 100° C. After completion of the reactionthe mixture was concentrated in vacuo. Residual thionyl chloride wasremoved by azeotropic distillation with toluene, to give2-chloro-isonicotinoyl chloride (15.33 g).

Example 4.3 Preparation of2-[(2-chloro-pyridine-4-carbonyl)-amino]-nicotinic acid methyl ester

A stirred and chilled (0° C.) mixture of 2-amino-nicotinic acid methylester (11 g, 72.3 mmol) in dichloromethane was treated sequentially withtriethylamine (11 mL, 79.5 mmol) and a solution of2-chloro-isonicotinoyl chloride (12.73 g, 72.3 mmol) in dichloromethane,such that the total volume of solvent was 80 mL. The reaction was warmedto room temperature and on completion of the reaction was quenched byaddition of water. The aqueous phase was separated and extracted withEtOAc. The combined organic phases were washed with brine, dried andconcentrated in vacuo. The residue was suspended in hot hexane, filteredwhile hot and the resulting solid recrystallised from EtOH, to give2-[(2-chloro-pyridine-4-carbonyl)-amino]-nicotinic acid methyl ester(12.76 g); ¹H-NMR (300 MHz, d₆-DMSO) 11.47 (1H, s), 8.62-8.67 (2H, m),8.20 (1H, unresolved dd), 7.99 (1H, s), 7.89 (1H, unresolved dd), 7.43(1H, dd), 3.72 (3H, s).

Example 4.4 Preparation of2-[(2-chloro-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester

A stirred solution of 2-[(2-chloro-pyridine-4-carbonyl)-amino]-nicotinicacid methyl ester (4 g, 13.72 mmol) in dry THF (60 mL), under nitrogen,was treated with borane-dimethyl sulphide complex (2M solution in THF,34 mL, 68.6 mmol). On completion of the reaction the mixture wascarefully poured into MeOH and the resulting mixture heated at refluxfor 30 minutes. The volatiles were removed in vacuo and the residuepartitioned between dilute aqueous sodium hydrogencarbonate solution anddichloromethane. The aqueous layer was extracted with dichloromethaneand the combined organic layers washed with brine, dried andconcentrated in vacuo. Purification was achieved by chromatography onIsolute® flash silica gel (Separtis) to give2-[(2-chloro-pyridin-4-ylmethylamino]-nicotinic acid methyl ester (0.76g); 1H-NMR (300 MHz, d₆-DMSO) 8.47 (1H, t), 8.30 (1H, d), 8.23 (1H,unresolved dd), 8.13 (1H, unresolved dd), 7.38 (1H, s), 7.30 (1H, d),6.68 (1H, dd), 4.73 (2H, d), 3.85 (3H, s).

Example 4.4 Preparation of2-[(2-chloro-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-nicotinamide

To a stirred and chilled (0° C.) suspension of2-methyl-2H-indazol-6-ylamine (1.52 g) in DCE (6 mL), under nitrogen,was added trimethylaluminium (2M solution in toluene, 5 mL, 9.37 mmol).This mixture was added dropwise to a stirred and chilled (0° C.)solution of 2-[(2-chloro-pyridin-4-ylmethylpamino]-nicotinic acid methylester (1.45 g, 5.21 mmol) in DCE (14.7 mL). The mixture was heated at100° C. for 2 hours before cooling to room temperature and quenching bypouring into aqueous sodium-potassium tartrate solution. The mixture wasextracted with EtOAc and the combined organic layers washed successivelywith dilute aqueous citric acid solution, dilute aqueous sodium hydrogencarbonate solution and brine, dried and concentrated in vacuo to give2-[(2-chloro-pyridin-4-ylmethylamino]-N-(2-methyl-2H-indazol-6-yl)-nicotinamide(1.58 g); ¹H-NMR (300 MHz, d₆-DMSO) 10.26 (1H, s), 8.40 (1H, t), 8.28(1H, d), 8.25 (1H, s), 8.06-8.12 (3H, m), 7.62 (1H, d), 7.35 (1H, s),7.30 (1H, unresolved dd), 7.27 (1H, unresolved dd), 6.68 (1H, dd), 4.67(2H, d), 4.10 (3H, s).

Example 5.0 Preparation of morpholine-4-carboxylic acid amide

To a stirred solution of morpholine (1.3 mL, 15 mmol) in isopropanol (30mL) at rt was added trimethylsilylisocyanate (2.8 mL, 21 mmol) and theresulting solution stirred overnight before the volatiles were removedin vacuo to give morpholine-4-carboxylic acid amide (2.0 g, quant.) as asolid; ¹H-NMR (300 MHz, d₆-DMSO) 6.00 (2H, s), 3.51-3.54 (4H, s),3.23-3.26 (4H, s).

Example 5.1 Preparation of (1-methyl-piperidin-4-yl)-urea

(1-methyl-piperidin-4-yl)-urea was prepared from1-methyl-piperidin-4-ylamine and trimethylsilylisocyanate, in analogy toExample 5.0; ¹H-NMR (300 MHz, d₆-DMSO) 5.86 (1H, d), 5.32 (2H, s),3.21-3.38 (1H, m), 2.58-2.67 (2H, m), 2.11 (3H, s), 1.88-1.98 (2H, m),1.65-1.72 (2H, m), 1.22-1.35 (2H, m).

The following examples detail the biological activity and use of thecompounds of the invention without the scope of the claimed compoundsbeing limited to these examples.

KDR Kinase Inhibition

Kinase activity was measured with a GST-kinase domain fusion constructof the KDR kinase according to the following protocol to obtainconcentration response curves. Components were added into amicrotiterplate in the following sequence: 10 μl of inhibitor inthreefold final concentration [3% DMSO in buffer (40 mM Tris Cl pH 7.5;1 mM DTT, 1 mM MnCl₂, 10 mM MgCl₂, 2.5 Promille Polyethyleneglycol20000)] and 10 μl of substrate mixture [24 μM ATP, 24 μg/mlpoly(Glu₄Tyr) in buffer, specific activity approx. 500 cpm/pmol³²P-γATP]. Reaction was started by adding 10 μl of enzyme preparationdiluted appropriately in buffer that contains 10 μM vanadate. Afterincubation for exactly 10 min the reaction was stopped by adding of 10μl stop solution (250 mM EDTA). 10 μl of the reaction mixture weretransferred to phosphocellulose filters. The filters were washed in 0.1%phosphoric acid, dried before meltilex scintillator was applied (Wallac,Perkin-Elmer) and the radioactivity was counted.

VEGFR-3 Autophosphorylation

MVECs (1,5×10⁶/well) of a low passage number were plated on collagen-Gcoated 48 well plates in EBM complete medium (including EGM-2,BD-Clonetech). 5 h later, medium was exchanged for EBM-2 without EGM-2but containing 0.2% BSA (EBM meager). 12 h later medium was removed, 250μl EBM-2 meager and the respective compound dilutions were added in 50μl EBM-2 meager. Solutions were carefully mixed and left for 5 min at 4°C. before the addition of 200 μl EBM-2 meager containing VEGF-C (finalconcentration in the assay is 5 nM; Reliatech, Braunschweig). Thesolution was then carefully mixed and incubated for 15 min at roomtemperature. The medium was removed and cells were washed twice withcold PBS/2 mM vanadate. Cells were then lysed with 100 μl Duschl buffer[50 mM Hepes pH 7,2; 150 mM NaCl; 1 mM MgCl₂; 1,5% Triton X-100; 10 mMNa-Pyrophosphate; 100 mM Na-Fluoride; 10% glycerol+(freshly added beforethe experiment) 2 mM Orthovanadate and 1 tablet per 50 ml Complete(Roche # 1836145)]

For the ELISA, Fluoronic MaxiSorp—MTP plates (# 3204006 Zinser)—werecoated overnight at 4° C. with Flt-4 antibody (Flt-4 (C-20) # sc-321Santa Cruz); 1 μg/ml in coating buffer: Na₂CO₃ pH 9,6 100 μl/well).After 3× washing with washing buffer (0,1% Tween 20 in Na₂HPO₄ pH 7.4)the wells were incubated with 250 μl blocking buffer (Roti Block 1/10from Roth, Karlsruhe for 1 h at room temperature). 3× Washing withwashing buffer was followed by addition of cell lysates and incubationover night at 4° C. Then wells were washed 3×, anti-phosophotyrosineantibody coupled to HRP(16-105; UPSTATE; dilution 1/20000 in TBST+3% TopBlock # 37766, Fluka) was added and incubated overnight at 4° C. Washingwith washing buffer (6×) preceded the addition of BM chemoluminescenceELISA reagent # 1582950 (Roche) and measurement of luminescence.

Cytochrome P450 Inhibition

The Cytochrome P450 isoenzyme inhibition was performed according to thepublication of Crespi et al. (Anal. Biochem., 1997, 248, 188-190) withuse of the baculovirus/insect cell-expressed, human Cytochrome P 450isoenzymes (2C9 and 2C19).

Selected results are presented in the following table: IC50 KDR-Kinase(VEGFR-2) IC50 CYP IC50 CYP Example (nM) 2C9 (μM) 2C19 (μM) 3.30 10 0.91.7 from WO 04/13102 3.40 40 1.1 2.3 from WO 04/13102 3.41 27 5.7 1.5from WO 04/13102 3.36 98 1.2 9.0 from WO 04/13102 1.0 10 11.7 >30.0 2.029 >30.0 >30.0The advantages of the compounds of the invention compared to knowncompounds can be readily demonstrated by the above studies.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius and, all parts and percentages are byweight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding European application No. 04090420.3filed Nov. 3, 2004, and U.S. Provisional Application Ser. No.60/626,918, filed Nov. 12, 2004, are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound of formula (I),

wherein: X is CH or N; W is hydrogen or fluorine; A, E and Qindependently of one another, are CH or N, whereby only a maximum of twonitrogen atoms are contained in the ring; R¹ is aryl or heteroaryl,which may be optionally substituted in one or more places in the sameway or differently with halogen, hydroxy, C₁-C₁₂-alkyl, C₂-C₆-alkenyl,C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may be substituted with —OR⁵ or —NR⁷R⁸,with the proviso that when R² and R³ are both —CH₃, R¹ is not any one ofthe following:

R² and R³ independently of one another, are C₁-C₁₂ alkyl optionallysubstituted with —OR; R⁴ is C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, aryl orheteroaryl; R⁵ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl or halo-CI—C₆-alkyl; R⁶ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl,halo-C₁-C₆-alkyl, aryl, or —NR⁷R⁸; R⁷ and R⁸ independently of oneanother, are hydrogen, —SO₂R⁶, —COR⁶, aryl, C₃-C₈-cycloalkyl,C₁-C₁₂-alkyl, halo-C₁-C₁₂-alkyl, or C₁-C₁₂-alkoxy, whereby C₁-C₁₂-alkylmay be optionally substituted with —OR⁵ or —N(CH₃)₂, or R⁷ and R⁸ mayalso be chosen in such a way as to provide a 3-8 membered cycloalkylring, which may optionally contain further heteroatoms, and may beoptionally substituted in one or more places in the same way ordifferently with halogen, cyano, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, ═O, —OR⁵, COR⁶, —SR⁴, —SOR⁴ or —SO₂R⁶; and as well asisomers, diastereoisomers, enantiomers, tautomers and salts thereof. 2.A compound as claimed in claim 1, wherein X is CH.
 3. A compound asclaimed in claim 1, wherein W is hydrogen.
 4. A compound as claimed in,wherein A, E, and Q each are CH.
 5. A compound as claimed in claim 1,wherein X is CH, W is hydrogen, and A, E, and Q each are CH.
 6. Acompound as claimed in claim 1, wherein R¹ is heteroaryl optionallysubstituted in one or more places in the same way or differently withhalogen, hydroxy, C₁-C₁₂-alkyl, C₂-C₆-alkenyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, ═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸,whereby C₁-C₁₂-alkyl may be substituted with —OR⁵ or —NR⁷R⁸, with theproviso that when R² and R³ are both —

CH₃, R¹ is not any one of the following:


7. A compound as claimed in claim 1, wherein R¹ heteroaryl substitutedin one or more places in the same way or differently with halogen,hydroxy, C₁-C₁₂-alkyl, C₂-C₆-alkenyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl,═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₂-alkylmay be substituted with —OR5 or —NR⁷R⁸, with the proviso that when R²and R³ are both CH₃, R is not any one of the following:


8. A compound as claimed in claim 1, wherein R¹ is

wherein R⁹ is hydrogen, halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may besubstituted with —OR⁵ or —NR⁷R⁸ and R¹⁰ is hydrogen or halogen;
 9. Acompound as claimed in claim 1, wherein R⁹ is hydrogen and R¹⁰ ishydrogen or halogen.
 10. A compound as claimed in claim 1, wherein R⁹and R¹⁰ are both hydrogen.
 11. A compound as claimed in claim 1 one ofclaims 15, wherein R¹ is

wherein R⁹ is hydrogen, halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may besubstituted with —OR or —NR⁷R⁸;
 12. A compound as claimed in claim 1,wherein R¹ is

wherein R⁹ is hydrogen.
 13. A compound as claimed in claim 1, wherein R²and R³ independently of one another, are C₁-C₁₂ alkyl optionallysubstituted with —OR⁵.
 14. A compound as claimed in claim 1, wherein R²and R³ independently of one another, are C₁-C₂ alkyl optionallysubstituted with —OR⁵.
 15. A compound as claimed in claim 1, wherein R²and R³ are both —CH₃.
 16. A compound as claimed in claim 1, wherein R⁴is C₁-C₁₂-alkyl.
 17. A compound as claimed in claim 1, wherein R⁴ is—CH₃.
 18. A compound as claimed in claim 1, wherein R⁵ is —CH₃ orhydrogen.
 19. A compound as claimed in claim 1, wherein R⁵ is hydrogen.20. A compound as claimed in claim 1, wherein R⁶ is C₁-C₁₂-alkyl or—NR⁷R⁸.
 21. A compound as claimed in claim 1, wherein R⁶ isC₁-C₁₂-alkyl.
 22. A compound as claimed in claim 1, wherein R⁶ is —CH₃.23. A compound as claimed in claim 1, wherein R⁷ and R⁸ independently ofone another, are hydrogen, —COR⁶, —SO₂R⁶, or C₁-C₁₂-alkyl.
 24. Acompound as claimed in claim 1, wherein R⁷ and R⁸ independently of oneanother, are hydrogen or C₁-C₁₂-alkyl.
 25. A compound as claimed inclaim 1, wherein R⁷ and R⁸ independently of one another, are hydrogen or—CH₃.
 26. A compound as claimed in claim 1, wherein: X is CH, w ishydrogen, A, E and Q each are CH, R¹ heteroaryl optionally substitutedin one or more places in the same way or differently with halogen,hydroxy, C₁-C₁₂-alkyl, C₂-C₆-alkenyl, C₁-C₁₂-alkoxy, halo-C I—C₆-alkyl,═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkylmay be substituted with —OR⁵ or —NR⁷R⁸, with the proviso that when R²and R³ are both —CH₃, R¹ is not any one of the following:

R² and R³ independently of one another, are C₁-C₂ alkyl optionallysubstituted with —OR⁵, R⁴ is C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, aryl orheteroaryl, R⁵ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl orhalo-C₁-C₆-alkyl, R⁶ hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, halo-CI—C₆-alkyl, aryl, or —NR⁷R⁸, R⁷ and R⁸ independently of one another, arehydrogen, —SO₂R⁶, —COR⁶, aryl, C₃-C₈-cycloalkyl, C₁-C₁₂-alkyl,halo-C₁-C₁₂-alkyl, or C₁-C₁₂-alkoxy, whereby C₁-C₁₂-alkyl may beoptionally substituted with —OR⁵ or —N(CH₃)₂, or R⁷ and R⁸ may also bechosen in such a way as to provide a 3-8 membered cycloalkyl ring, whichmay optionally contain further heteroatoms, and may be optionallysubstituted in one or more places in the same way or differently withhalogen, cyano, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —OR⁵,COR⁶, —SR⁴, —SOR⁴ or —SO₂R⁶, and as well as isomers, diastereoisomers,enantiomers, tautomers and salts thereof.
 27. A compound as claimed inclaim 1, wherein: X is CH, W is hydrogen, A, E and Q each are CH, R¹heteroaryl substituted in one or more places in the same way ordifferently with halogen, hydroxy, C₁-C₁₂-alkyl, C₂-C₆-alkenyl,C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may be substituted with —OR⁵ or —NR⁷R⁸,with the proviso that when R² and R³ are both —CH₃, R¹ is not any one ofthe following:

R² and R³ independently of one another, are C₁-C₂ alkyl optionallysubstituted with —OR⁵; R⁴ is C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, aryl orheteroaryl, R⁵ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl orhalo-C₁-C₆-alkyl, R⁶ hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl,halo-C₁-C₆-alkyl, aryl, or —NR⁷R⁸, R⁷ and R⁸ independently of oneanother, are hydrogen, —SO₂R⁶, —COR⁶, aryl, C₃-C₈-cycloalkyl,C₁-C₁₂-alkyl, halo-C₁-C₁₂-alkyl, or C₁-C₁₂-alkoxy, whereby C₁-C₁₂-alkylmay be optionally substituted with —OR⁵ or —N(CH₃)₂, or R⁷ and R⁸ mayalso be chosen in such a way as to provide a 3-8 membered cycloalkylring, which may optionally contain further heteroatoms, and may beoptionally substituted in one or more places in the same way ordifferently with halogen, cyano, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, ═O, —OR⁵, COR⁶, —SR⁴, —SOR⁴ or —SO₂R⁶, and as well asisomers, diastereoisomers, enantiomers, tautomers and salts thereof. 28.A compound as claimed in claim 1, wherein: X is CH, W is hydrogen, A, Eand Q each are CH,

R¹ is wherein R⁹ is hydrogen, halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may besubstituted with —OR⁵ or —NR⁷R⁸ and R¹⁰ is hydrogen or halogen; R² andR³ independently of one another, are C₁-C₂ alkyl optionally substitutedwith —OR⁵; R⁴ is C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, aryl or heteroaryl, R⁵is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl or halo-C₁-C₆-alkyl, R⁶hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, halo-C I—C₆-alkyl, aryl, or—NR⁷R⁸, R⁷ and R⁸ independently of one another, are hydrogen, —SO₂R⁶,—COR⁶, aryl, C₃-C₈-cycloalkyl, C₁-C₁₂-alkyl, halo-C₁-C₁₂-alkyl, orC₁-C₁₂-alkoxy, whereby C₁-C₁₂-alkyl may be optionally substituted with—OR⁵ or —N(CH₃)₂, or R⁷ and R⁸ may also be chosen in such a way as toprovide a 3-8 membered cycloalkyl ring, which may optionally containfurther heteroatoms, and may be optionally substituted in one or moreplaces in the same way or differently with halogen, cyano, C₁-C₁₂-alkyl,C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —OR⁵, COR⁶, —SR⁴, —SOR⁴ or —SO₂R⁶,and as well as isomers, diastereoisomers, enantiomers, tautomers andsalts thereof.
 29. A compound as claimed in claim 1, wherein: X is CH, Wis hydrogen, A, E and Q each are CH, R¹ is

wherein R⁹ is hydrogen and R¹⁰ is hydrogen or halogen, R² and R³independently of one another, are C₁-C₂ alkyl optionally substitutedwith —OR⁵, and as well as isomers, diastereoisomers, enantiomers,tautomers and salts thereof.
 30. A compound as claimed in claim 1,wherein: X is CH, W is hydrogen, A, E and Q each are CH, R¹ is

wherein R⁹ is hydrogen, halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may besubstituted with —OR⁵ or —NR⁷R⁸, R² and R³ independently of one anotherare unsubstituted C₁-C₂ alkyl, and as well as isomers, diastereoisomers,enantiomers, tautomers and salts thereof.
 31. A compound as claimed inclaim 1, wherein: X is CH, W is hydrogen, A, E and Q each are CH, R¹ is

wherein R⁹ is hydrogen, R² and R³ are both unsubstituted C₁-C₂ alkyl,and as well as isomers, diastereoisomers, enantiomers, tautomers andsalts thereof.
 32. A compound as claimed in claim 1, selected from thegroup consisting of:2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide2-{[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide2-({2-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide2-({2-[3-(2-methoxy-ethyl)₃-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide2-{[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(4-fluoro-2-methyl-2H-indazol-6-yl)benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(7-methoxy-isoquinolin-3-yl)-benzamide6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methyl-2H-indazole-3-carboxylicacid methyl ester2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-benzotriazol-5-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-7-yl)benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-3a,7a-dihydro-1H-indazol-4-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro-2-methyl-2H-indazol-4-yl)benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-2-methyl-2H-indazol-7-yl)benzamide6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-1-methyl-1H-indazole-3-carboxylicacid methyl ester2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-hydroxymethyl-1-methyl-1H-indazol-6-yl)benzamideN-(3,6-difluoro-quinolin-2-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-sulfamoyl-phenyl)-benzamideN-(2,3-dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxymethyl-2-methyl-2H-indazol-6-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxymethyl-1-methyl-1H-indazol-6-yl)-benzamide6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-1-methyl-1H-indazole-3-carboxylicacid methylamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-1-methyl-1H-indazol-5-yl)benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-2-methyl-2H-indazol-5-yl)benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro-1-methyl-1H-indazol-4-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-quinolin-3-yl-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-fluoro-6-methoxy-quinolin-2-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methyl-3H-benzoimidazol-5-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-1H-benzoimidazol-5-yl)-benzamide2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methanesulfonyl-phenyl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide,and as well as isomers, diastereoisomers, enantiomers, tautomers andsalts thereof.
 33. A pharmaceutical agent comprising at least onecompound of formula (I) according to claim
 1. 34. A pharmaceutical agentcomprising at least one compound of formula (I) according to claim 1 andat least one pharmaceutically acceptable carrier.
 35. A pharmaceuticalagent according to claim 33 for use in the treatment of diseasesassociated with persistant angiogenesis and/or diseases associated withexcessive lymphangiogenesis.
 36. A pharmaceutical agent according toclaim 33 for use in the treatment of tumor- or metastases-growth;psoriasis; Karposi's sarcoma; restenosis including stent-inducedrestenosis; Crohn's disease; Hodgkin's disease; leukemia; arthritisincluding rheumatoid arthritis, hemangioma, angiofibroma; endometriosis;eye diseases including diabetic retinopathy, neovascular glaucoma;corneal transplants; renal diseases, including glomerulonephritis,diabetic nephropathy, malignant nephrosclerosis, thromboticmicroangiopathic syndrome, transplant rejections and glomerulopathy;fibrotic diseases, including cirrhosis of the liver; mesangial cellproliferative diseases; arteriosclerosis; injuries to the nerve tissue,and for inhibiting the reocclusion of vessels after balloon cathetertreatment; in vascular prosthetics or after mechanical devices are usedto keep vessels open, as immunosuppresive agent for supporting scar-freehealing; senile keratosis; contact dermatitis; and asthma.
 37. Apharmaceutical agent according to claim 33 for use as VEGF receptorkinase 3-inhibitors of lymphangiogenesis.
 38. A compound of formula (I)according to claim 1 for use in a method for the treatment of the humanor animal body.
 39. A compound of formula (I) according to claim 1 foruse in the preparation of a pharmaceutical product for the treatment ofa disease for which an inhibition of angiogenesis and/orlymphangiogenesis and/or the VEGF receptor kinases is beneficial.
 40. Acompound of formula (I) according to claim 1 for use as an inhibitor ofthe tyrosine kinases VEGFR-1 and VEGFR-2.
 41. A compound of generalformula (III),

in which A, E, Q, W, X, R² and R³, are as defined in formula (I) andR^(y) is H or C₁-C₆-alkyl, as intermediate for the preparation of acompound of formula (I).
 42. A compound as claimed in claim 41, whereinR^(y) is H or C₁-C₂-alkyl.
 43. The use of a compound as claimed in claim41, as intermediate for the preparation of a compound of formula (I).44. A process for the preparation of a compound of formula (I),

wherein all substituents are as described in claim 1, in which acompound of formula (III),

in which A, E, Q. W X, R² and R³, are as defined in formula (I) andR^(y) is H or C₁-C₆-alkyl, is reacted with an amine of formula R¹NH₂ inwhich R¹ is as defined in claim
 1. 45. A process for the preparation ofa compound of formula (I),

wherein all substituents are as described in claim 1, in which acompound of formula (II),

wherein A, E, Q. W. X, and R¹ are as defined in claim 1 and M stands forhalogen, is: (i) first converted to an amine and subsequently convertedto a compound of formula (I) by reaction with a carbamoyl chloride offormula ClCONR²R³, wherein R² and R³ are as defined in claim 1; oralternatively, (ii) reacted with a compound of formula H₂NCONR²R³,wherein R² and R³ are as defined in claim 1; or alternatively, (iii)first converted to an amine, then converted to a compound of formula (I)by first reacting with a compound of formula ClCO₂Ph and then reactingwith a compound of formula HNR²R³, wherein R² and R³ are as defined inclaim
 1. 46. A process as claimed in claim 45, wherein in which thecompound of formula (II) is reacted with a compound of formulaH₂NCONR²R³, wherein R² and R³ are independently of one another, areC₁-C₁₂ alkyl optionally substituted with —OR⁵.